Currently, very little is known regarding tissue-specific gene regulation during the later stages of tooth development, especially those associated with dentin mineralization. Recent studies have identified transforming growth factor-beta 1 (TGF21) as a potential modulator of primary dentin extracellular matrix (DECM) formation. TGF21 has been shown to initiate odontoblast cytodifferentiation from immature dental papilla mesenchymal cells. Initially secreted by enamel organ epithelium, TGF21 has been shown to be upregulated in dentin-producing odontoblasts during primary dentinogenesis and become incorporated into the DECM. In mature odontoblasts, however, TGF21 has been shown to downregulate DECM proteins such as dentin matrix protein-1 (DMP-1) and dentin sialophosphoprotein (DSPP), two of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family of bone/dentin matrix proteins. Matrix extracellular phosphoglycoprotein (MEPE), the least characterized SIBLING member in teeth, seems to have controversial roles in mineralization. Preliminary studies demonstrate that TGF21 dysregulates SIBLING protein and gene expression in the dentin layer and in pulp cells of a novel transgenic mouse model for Camurati-Engelmann disease (CED). CED, though rare, is most often due to a point mutation in the TGFB1 gene leading to overexpression of the mature, active TGF21 molecule. Patients with CED present with severe bone thickening and subsequent soft tissue compression. Transmitted through autosomal dominant inheritance, CED in humans has not been previously reported to be associated with dental abnormalities. Our hypothesis is that the transgenic CED mouse model displays abnormal dentin formation as mediated by altered expression of the SIBLINGs, in particular MEPE, caused by the overexpression of mature TGF21. The specific aims seek to identify the signaling effects that overexpression of TGF21 has on dentin matrix formation and maturation, to clarify the function of MEPE in dentin mineralization, and to determine the way in which TGF21 regulates Mepe expression. Novel mouse models and in vitro systems will be used and characterized by way of radiographic and mineral density microcomputed tomography examinations, along with biochemical and functional assays. The information obtained from these studies will provide a foundation for understanding the molecular mechanisms involved in both normal and pathological dentin development. Eventually the proposed studies will facilitate the development of novel diagnostic tools and therapeutic treatments for patients with dental caries, various tooth/bone mineralization disorders, or syndromes with altered dentin formation. This research will elucidate the role of tooth/bone matrix material properties in oral and skeletal health and disease. PUBLIC HEALTH RELEVANCE: The proposed research for my graduate thesis work in the UAB DMD/PhD (Molecular and Cellular Pathology) program at UAB School of Dentistry will focus on dentin mineralization, particularly, the function of matrix extracellular phosphoglycoprotein (MEPE), a protein found especially in bones and teeth, as regulated by a common component in most tissues, transforming growth factor-21 (TGF21). These studies will contribute to our knowledge of how mineralization occurs normally in bones and teeth, which factors enhance or reduce the mineralization process specifically in the dentin layer of teeth, and which molecular events disrupt bone and tooth formation in human mineralization disorders. This work has potential to lead to the development of novel therapeutics for individuals with genetic or non-hereditary tissue mineralization disorders (e.g. excessive thickening of long bones, abnormal dental pulp calcification or tooth development).